[Analysis of gene mutation of early onset epileptic spasm with unknown reason].

Objective: To summarize the gene mutation of early onset epileptic spasm with unknown reason. Method: In this prospective study, data of patients with early onset epileptic spasm with unknown reason were collected from neurological department of Children's Hospital of Fudan University between March 2016 and December 2016. Patients with known disorders such as infection, metabolic, structural, immunological problems and known genetic mutations were excluded. Patients with genetic disease that can be diagnosed by clinical manifestations and phenotypic characteristics were also excluded. Genetic research methods included nervous system panel containing 1 427 epilepsy genes, whole exome sequencing (WES), analysis of copy number variation (CNV) and karyotype analysis of chromosome. The basic information, phenotypes, genetic results and the antiepileptic treatment of patients were analyzed. Result: Nine of the 17 cases with early onset epileptic spasm were boys and eight were girls. Patients' age at first seizure onset ranged from 1 day after birth to 8 months (median age of 3 months). The first hospital visit age ranged from 1 month to 2 years (median age of 4.5 months). The time of following-up ranged from 8 months to 3 years and 10 months. All the 17 patients had early onset epileptic spasm. Video electroencephalogram was used to monitor the spasm seizure. Five patients had Ohtahara syndrome, 10 had West syndrome, two had unclear classification. In 17 cases, 10 of them had detected pathogenic genes. Nine cases had point mutations, involving SCN2A, ARX, UNC80, KCNQ2, and GABRB3. Except one case of mutations in GABRB3 gene have been reported, all the other cases had new mutations. One patient had deletion mutation in CDKL5 gene. One CNV case had 6q 22.31 5.5MB repeats. Ten cases out of 17 were using 2-3 antiepileptic drugs (AEDs) and the drugs had no effect. Seven cases used adrenocorticotropic hormone (ACTH) and prednisone besides AEDs (a total course for 8 weeks). Among them, five cases had no effect and two cases were seizure free recently. A case with GABRB3 (C.905A>G) had seizure controlled for 3 mouths. A case with ARX (C.700G>A) had seizure controlled for 6 mouths. Conclusion: The early onset epileptic spasm with unknown reason is highly related to genetic disorders. A variety of genetic mutations, especially new mutations were found. Genetic heterogeneity of epileptic spasm is obvious.目的： 探究不明病因早发癫痫性痉挛的遗传性病因。 方法： 前瞻性收集2016年3至12月复旦大学附属儿科医院神经科门诊就诊的17例不明病因早发癫痫性痉挛的患儿（男9例，女8例，就诊年龄1~8月龄），排除各种已知的病因（如感染性、代谢性、结构性、免疫性病因），排除临床表型及疾病特征可诊断的遗传相关疾病；进行神经系统Panel（包含1 427个癫痫基因）、全外显子测序、拷贝数变异分析、染色体核型分析。分析病例基本信息、病例表型特征、病例遗传结果以及药物治疗随访。 结果： 17例患儿中，男9例，女8例；发病年龄范围为生后1 d~8月龄（中位年龄为3月龄），首次就诊年龄1~24月龄（中位年龄4.5月龄），随访时间为8~46月龄。17例患儿均为早发癫痫性痉挛；所有患儿视频脑电图检查至少1次监测到癫痫性痉挛发作，其中大田原综合征5例，West综合征10例，综合征分类不确定2例。17例中检出10例致病基因，点突变9例，涉及基因为SCN2A、ARX、UNC80、KCNQ2、GABRB3，除1例GABRB3基因突变位点已报道，8例为未报道的新发突变位点；碱基缺失1例，涉及基因为CDKL5，拷贝数变异（CNV）1例，为6q 22.31 5.5MB重复。17例病例中10例仅使用2~3种抗癫痫药物治疗，均药物治疗无效；7例抗癫痫药物联合促肾上腺皮质激素加泼尼松治疗（总疗程8周），5例治疗无效，2例近期癫痫发作得到控制，1例不发作3个月，患儿为GABRB3（c.905A>G）突变；1例不发作6个月，患儿为ARX（c.700G>A）突变。 结论： 不明病因早发癫痫性痉挛的遗传病因相关性高，遗传变异基因谱广泛，新发突变为主，癫痫性痉挛遗传异质性明显。.